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A Trial of TH-302 in Combination With Doxorubicin Versus Doxorubicin Alone to Treat Patients With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01440088
Recruitment Status : Completed
First Posted : September 26, 2011
Last Update Posted : June 2, 2016
Sarcoma Alliance for Research through Collaboration (SARC)
Information provided by (Responsible Party):
Threshold Pharmaceuticals

Brief Summary:
The purpose of this study is to determine whether TH-302 in combination with Doxorubicin is safe and effective in the treatment of Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma.

Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Drug: TH-302 in Combination with Doxorubicin Drug: Doxorubicin Phase 3

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

Detailed Description:
TH-302 is designed to target the hypoxic regions of tumors which are generally located distant from tumor vessels. Doxorubicin has poor tissue penetration and targets the regions of tumors that are located in proximity to the tumor vessels. The presence of hypoxia in solid tumors is associated with a more malignant phenotype and resistance to chemotherapy. The hypoxia-activated prodrug, TH-302, is designed to selectively target the hypoxic microenvironment. Soft tissue sarcomas have evidence supporting the presence of hypoxia based on pO2 histography, F-MISO and gene expression profiling. There is an absence of therapeutic options for subjects with soft tissue sarcoma. Combining doxorubicin with TH-302 may enable the targeting of both the normoxic and hypoxic regions of soft tissue sarcoma.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 640 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase 3, Multicenter, Open-Label Study Comparing TH-302 in Combination With Doxorubicin vs. Doxorubicin Alone in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma
Study Start Date : September 2011
Actual Primary Completion Date : December 2015
Actual Study Completion Date : May 2016

Arm Intervention/treatment
Experimental: TH-302 in Combination with Doxorubicin Drug: TH-302 in Combination with Doxorubicin

300 mg/m2 of TH-302 will be administered by IV infusion over 30-60 minutes on Days 1 and 8 of a 21-day cycle.

Doxorubicin may be delivered as a bolus administration or as a continuous infusion administration; administration schedule must be specified prior to enrollment.

Doxorubicin bolus administration: 75 mg/m2 administered by bolus injection starting on Day 1 of a 21-day cycle.

Doxorubicin continuous administration: 75 mg/m2 administered by continuous IV infusion over 48-96 hours starting on Day 1 of a 21-day cycle.

Doxorubicin administration will start between 2 to 4 hours after completion of the TH-302 infusion when used in combination with TH-302.

Active Comparator: Doxorubicin Drug: Doxorubicin

Doxorubicin may be delivered as a bolus administration or as a continuous infusion administration; administration schedule must be specified prior to enrollment.

Doxorubicin bolus administration: 75 mg/m2 administered by bolus injection starting on Day 1 of a 21-day cycle.

Doxorubicin continuous administration: 75 mg/m2 administered by continuous IV infusion over 48-96 hours starting on Day 1 of a 21-day cycle.

Primary Outcome Measures :
  1. Efficacy of TH-302 in combination with doxorubicin [ Time Frame: 2 years ]
    Efficacy will be determined by overall survival in subjects with locally advanced unresectable or metastatic soft tissue sarcoma previously untreated with chemotherapy compared with doxorubicin alone

Secondary Outcome Measures :
  1. Safety of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma compared with doxorubicin alone [ Time Frame: 2 years ]
    To investigate the pharmacokinetics of TH-302, Br-IPM, doxorubicin, and doxorubicinol in plasma

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male or female ≥ 15 years of age
  • Ability to understand the purposes and risks of the study and has signed or, if appropriate, the subject's parent or legal guardian has signed a written informed consent form approved by the investigator's IRB/Ethics Committee
  • Pathologically confirmed diagnosis of soft tissue sarcoma of the following histopathologic types:

    • Synovial sarcoma
    • High grade fibrosarcoma
    • Undifferentiated sarcoma; sarcoma not otherwise specified (NOS)
    • Liposarcoma
    • Leiomyosarcoma (excluding GIST)
    • Angiosarcoma (excluding Kaposi's sarcoma)
    • Malignant peripheral nerve sheath tumor
    • Pleomorphic Rhabdomyosarcoma
    • Myxofibrosarcoma
    • Epithelioid sarcoma
    • Undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma (MFH) (including pleomorphic, giant cell, myxoid and inflammatory forms)
  • Locally advanced unresectable or metastatic disease with no standard curative therapy available and for whom treatment with single agent doxorubicin is considered appropriate.
  • Recovered from reversible toxicities of prior therapy
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy of at least 3 months
  • Acceptable liver, renal, hematological and cardiac function
  • All women of childbearing potential must have a negative serum pregnancy test and all subjects must agree to use effective means of contraception

Exclusion Criteria:

  • Prior systemic therapy for advanced or metastatic disease (neoadjuvant therapy followed by surgical resection and adjuvant therapy permitted). Palliative radiotherapy to non-target lesions is allowed if completed at least two weeks prior to study entry
  • Low grade tumors according to standard grading systems
  • Prior therapy with ifosfamide or cyclophosphamide or other nitrogen mustards
  • Prior therapy with an anthracycline or anthracenedione
  • Prior mediastinal/cardiac radiotherapy
  • Current use of drugs with known cardiotoxicity or known interactions with doxorubicin
  • Anti-cancer treatment with radiation therapy, neoadjuvant or adjuvant chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 4 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C). Palliative radiotherapy to non-target lesions is allowed, is completed at least two weeks prior to study entry.
  • Significant cardiac dysfunction precluding treatment with doxorubicin
  • Seizure disorders requiring anticonvulsant therapy unless seizure-free for the last year
  • Known brain metastases (unless previously treated and well controlled for a period of ≥ 3 months)
  • Previously treated malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years
  • Severe chronic obstructive or other pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia
  • Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
  • Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
  • Prior therapy with a hypoxic cytotoxin
  • Subjects who participated in an investigational drug or device study within 28 days prior to study entry
  • Known infection with HIV, hepatitis B, or hepatitis C
  • Subjects who have exhibited allergic reactions to a structural compound similar to TH-302,doxorubicin or their excipients
  • Females who are pregnant or breast-feeding
  • Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
  • Unwillingness or inability to comply with the study protocol for any reason

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01440088

Hide Hide 92 study locations
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United States, Arizona
Mayo Arizona
Scottsdale, Arizona, United States, 85259
Arizona Cancer Center
Tucson, Arizona, United States, 85719
United States, California
USC-Norris Comprehensive Cancer Center
Los Angeles, California, United States, 90033
University of California, Los Angeles
Los Angeles, California, United States, 90095-6901
Sarcoma Oncology Center
Santa Monica, California, United States, 90403
Stanford Comprehensive Cancer Center
Stanford, California, United States, 94305
United States, District of Columbia
Georgetown University Hospital
Washington, District of Columbia, United States, 20007
Washington Cancer Institute
Washington, District of Columbia, United States, 20010
United States, Florida
South Florida Center for Gynecologic Oncology
Boca Raton, Florida, United States, 33487
Mayo Clinic-Florida-Cancer Clinical Studies Unit
Jacksonville, Florida, United States, 32224
MD Anderson Cancer Center Orlando
Orlando, Florida, United States, 32806
H.Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612
United States, Georgia
Winship Cancer Institute of Emory University, Midtown Campus
Atlanta, Georgia, United States, 30322
United States, Idaho
Kootenai Health - Kootenai Cancer Center
Coeur d`Alene, Idaho, United States, 83814
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Rush University Medical Center
Chicago, Illinois, United States, 60612
Oncology Specialists
Park Ridge, Illinois, United States, 60068
United States, Indiana
Indiana University Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Iowa
University of Iowa Health Care - University of Iowa Hospital
Iowa City, Iowa, United States, 52242
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Dana Farber Cancer Institute Center for Sarcoma and Bone Oncology
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan Cancer Center
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Rochester
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Bronx, New York, United States, 10461
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10031
Columbia University Medical Center
NY, New York, United States, 10032
United States, North Carolina
Carolinas Hematology-oncology Associates-Blumenthal Cancer Center
Charlotte, North Carolina, United States, 28203
Duke University Medical Center
Durham, North Carolina, United States, 27710
Wake Forest University Baptist Medical Center
Winston Salem, North Carolina, United States, 27157
United States, Ohio
University Hospitals Seidman Cancer Center
Cleveland, Ohio, United States, 44106
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
The Arthur G. James Cancer Hospital and Richard J Solove Research Institue, The Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43202
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Pennsylvania Oncology Hematology Associates
Philadelphia, Pennsylvania, United States, 19106
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
University of Pittsburg Medical Center
Pittsburg, Pennsylvania, United States, 15232
United States, South Carolina
MUSC - Hollings Cancer Center
Charleston, South Carolina, United States, 29425
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Vermont
University of Vermont
Burlington, Vermont, United States, 05405
United States, Virginia
Virginia Commonwealth Universtiy-Massey Cancer Center
Richmond, Virginia, United States, 23298
United States, Washington
University of Washington Cancer Center
Seattle, Washington, United States, 98109
United States, Wisconsin
Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
University Klinikum Graz
Graz, Austria, A-8036
Univ. Klinik fur Innere Medizin I Internistische Onkologie Medizinische Universitat Innsbruck
Innsbruck, Austria, A-6020
Allgemeines Krankenhaus Wien
Wien, Austria, A-1090
Universitaire Ziekenhuizen (UZ) Leuven - Gasthuisberg
Leuven, Belgium, 3000
Canada, Ontario
Juravinski Cancer Centre at Hamilton Health Sciences - Department of Medicine
Hamilton, Ontario, Canada, L8V5C2
Canada, Quebec
McGill University Health Centre
Montreal, Quebec, Canada, H3G 1A4
Tom Baker Cancer Centre
Calgary, Canada, T2N4N2
Cross Cancer Institute
Edmonton, Canada, T6G1Z2
Ottawa Health Research Institue
Ottawa, Canada, K1H8L6
BCCA- Vancouver Cancer Centre - Division of Medical Oncology
Vancouver, Canada, V5Z4E6
Cancer Care Manitoba
Winnipeg, Canada, R3E0V9
University Hospital Herlev at Copenhagen
Herlev, Copenhagen, Denmark, 2730
ICO Rene Gauducheau
Saint Herblain Cedex, Nantes, France, 44805
Institut Bergonie
Bordeaux, France, 33076
Departement d'Oncologie Medicale
Dijon, France, 21079
Centre Leon Berard
Lyon, France, 69008
Département d'Oncologie Moléculaire, Institut Paoli-Calmettes (IPC) and U119 Inserm
Marseille, France, 13009
Centre Antoine Lacassagne
Nice, France
CHU Strasbourg
Strasbourg, France, 67098
Institut Claudius Regaud
Toulouse Cedex, France, 31052
HELIOS Klinikum Berlin-Buch
Berlin, Germany, 13125
Helios Klinikum Bad Saarow, Department of Hematology, Oncology, and Palliative Care, Sarcoma Center Berlin-Brandenburg
Berlin, Germany, 15526
Universitätsklinikum Essen
Essen, Germany, 45122
Krankenhaus Nordwest GmbH
Frankfurt, Germany
Medizinische Hochschule Hannover (MHH) - Klinik fuer Haemonstaseologie, Onkologie und Stammzelltransplantation
Hannover, Germany, 30625
Div. of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center
Mannheim, Germany, D-68165
Wilhelm's University, Universitatsklinikum Muenster, Medizinische Klinik und Poliklinik A, Albert-Schweitzer-Campus 1
Munster, Germany, 48149
Magyar Honvedseg Honvedkorhaz, Onkologiai Osztaly
Budapest, Hungary, H-1062
Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Megyei Onkologiai Kozpont
Szolnok, Hungary, H-5004
Sharette Institute of Oncology, Hadassah-Hebrew University Medical Center, Hadassah Medical Org-Ein Karem
Kiryat Hadassah, Jerusalem, Israel, 91120
IRCCS Centro di Riferimento Oncologico-Struttura Operativa
Aviano, Pordenone, Italy, 33081
Fondazione del Piemonte per l'Oncologia, Instituto per la Ricerca e la Cura del cancro (I.R.C.C.), Dipartimento Oncologico, Direzione Operativa Oncologia Medica a Direzione Universitaria
Candiolo, Torino, Italy, 10060
Centro di Riferimento Oncologico (CRO)
Aviano, Italy, 33081
Azienda Ospedaliera Garibaldi
Catania, Italy, 95122
Azienda Ospedaliero Universitaria-Policlinico Paolo Giacco
Palermo, Italy, 90127
ASL TO/2 di TORINO_Presidio Sanitario Gradenigo, S.C. di Oncologia
Torino, Italy, 10149
Wojewodzkie Centrum Onkologii
Gdansk, Poland, 80-219
Centrum Onkologii Instytut im M. Sklodowskiej-Curie
Krakow, Poland, 31-115
Centrum Onkologii-Instytut im. M. Sklodowskiej-Curie
Warszawa, Poland, 02-781
Russian Federation
GUZ "Regional Oncology Dispensay", Kazan
Kazan, Russian Federation, 420029
ROTSN RAMS them. Н.Н.Блохина NN Blokhin
Moscow, Russian Federation, 115478
FGU Moscow Research Institute of Oncology named after P.A. Hertzen of Rosmedtechnology
Moscow, Russian Federation, 125284
H.U. Canarias, Hospital Universitario de Canarias. Servicio de Oncología Médica
Tenerife, Canarias, Spain, 38320
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain, 08041
Institut Catala d'Oncologia
Barcelona, Spain, 08907
Hospital Sant Joan de Deu, Department de Oncologia
Barcelona, Spain, 08950
Hospital Universitario Ramón y Cajal.
Madrid, Spain, 28034
Universidad Complutense Madrid Facultad de Medicina - Hospital Universitario 12 de Octubre, Servicio de Oncologia Medica Hospital Universitario 12 de Octubre
Madrid, Spain, 28034
Sponsors and Collaborators
Threshold Pharmaceuticals
Sarcoma Alliance for Research through Collaboration (SARC)
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Principal Investigator: William Tap, MD Memorial Sloan Kettering Cancer Center
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Threshold Pharmaceuticals Identifier: NCT01440088    
Other Study ID Numbers: TH-CR-406/SARC021
First Posted: September 26, 2011    Key Record Dates
Last Update Posted: June 2, 2016
Last Verified: June 2016
Keywords provided by Threshold Pharmaceuticals:
Locally Advanced Soft Tissue Sarcoma
Metastatic Soft Tissue Sarcoma
Additional relevant MeSH terms:
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Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action